Enantioselective synthesis of quaternary 3,4-dihydroisoquinolinones via Heck carbonylation reactions: development and application to the synthesis of Minalrestat analogues?

Chemical Science Pub Date: 2019-09-03 DOI: 10.1039/C9SC03406D

Abstract

Minalrestat and its analogues represent structurally novel aldose reductase inhibitors, and the asymmetric synthesis of such pharmaceutically privileged molecules has not been reported yet. We have developed a palladium-catalyzed enantioselective intramolecular carbonylative Heck reaction by using formate esters as the source of CO, which represents the first enantioselective synthesis of quaternary 3,4-dihydroisoquinolines. The reaction provides a facile and efficient method for the synthesis of enantiopure nitrogen-containing heterocyclic compounds bearing an all-carbon quaternary stereocenter. The reaction has been successfully applied to the first asymmetric synthesis of Minalrestat analogues.

Graphical abstract: Enantioselective synthesis of quaternary 3,4-dihydroisoquinolinones via Heck carbonylation reactions: development and application to the synthesis of Minalrestat analogues
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